Examination of subjects using photon migration with high directionality techniques

ABSTRACT

A spectroscopic method and system for examination of biological tissue includes multiple input ports optically connected to at least one light source, multiple detection ports optically connected to at least one detector, a radiation pattern controller coupled to the light source and detector, and a processor. The multiple input ports are arranged to introduce light at input locations into biological tissue and the multiple detection ports are arranged to collect light from detection locations of the biological tissue. The radiation pattern controller is constructed to control patterns of light introduced from the multiple input ports and constructed to control detection of light migrating to the multiple detection ports. The processor is operatively connected to the radiation pattern controller and connected to receive detector signals from the detector, and is constructed to examine a tissue region based on the introduced and detected light patterns.

BACKGROUND OF THE INVENTION

[0001] This invention relates to examination and imaging of biologicaltissue using visible or infra-red radiation.

[0002] Traditionally, potentially harmful ionizing radiation (forexample, X-ray or γ-ray) has been used to image biological tissue. Thisradiation propagates in the tissue on straight, ballistic tracks, i.e.,scattering of the radiation is negligible. Thus, imaging is based onevaluation of the absorption levels of different tissue types. Forexample, in roentgenography the X-ray film contains darker and lighterspots. In more complicated systems, such as computerized tomography(CT), a cross-sectional picture of human organs is created bytransmitting X-ray radiation through a section of the human body atdifferent angles and by electronically detecting the variation in X-raytransmission. The detected intensity information is digitally stored ina computer which reconstructs the X-ray absorption of the tissue at amultiplicity of points located in one cross-sectional plane.

[0003] Near infra-red radiation (NIR) has been used to studynon-invasively the oxygen metabolism in tissue (for example, the brain,finger, or ear lobe). Using visible, NIR and infra-red (IR) radiationfor medical imaging could bring several advantages. In the NIR or IRrange the contrast factor between a tumor and a tissue is much largerthan in the X-ray range. In addition, the visible to IR radiation ispreferred over the X-ray radiation since it is non-ionizing; thus, itpotentially causes fewer side effects. However, with lower energyradiation, such as visible or infra-red radiation, the radiation isstrongly scattered and absorbed in biological tissue, and the migrationpath cannot be approximated by a straight line, making inapplicablecertain aspects of cross-sectional imaging techniques.

[0004] Recently, certain approaches to NIR imaging have been suggested.One approach undertaken by Oda et al. in “Non-Invasive HemoglobinOxygenation Monitor and Computerized Tomography of NIR Spectrometry,”SPIE Vol. 1431, p. 284, 1991, utilizes NIR radiation in an analogous wayto the use of X-ray radiation in an X-ray CT. In this device, the X-raysource is replaced by three laser diodes emitting light in the NIRrange. The NIR-CT uses a set of photomultipliers to detect the light ofthe three laser diodes transmitted through the imaged tissue. Thedetected data are manipulated by a computer of the original X-ray CTscanner system in the same way as the detected X-ray data would be.

[0005] Different approaches were suggested by S. R. Arriadge et al. in“Reconstruction Methods for Infra-red Absorption Imaging,” SPIE Vol.1431, p. 204, 1991; F. A. Grünbaum et al. in “Diffuse Tomography,” SPIEVol. 1431, p. 232, 1991; B. Chance et al., SPIE Vol. 1431 (1991), p. 84,p. 180, and p. 264; and others who recognized the scattering aspect ofthe non-ionizing radiation and its importance in imaging. None of thosetechniques have fully satisfied all situations.

[0006] In summary, there continues to be a need for an improved imagingsystem which utilizes visible or IR radiation of wavelengths sensitiveto endogenous or exogenous pigments.

SUMMARY OF THE INVENTION

[0007] The invention relates to systems and methods for spectroscopicexamination of a subject positioned between input and detection ports ofthe spectroscopic system applied to the subject.

[0008] According to one aspect of the invention, a spectroscopic systemincludes at least one light source adapted to introduce, at multipleinput ports, electromagnetic non-ionizing radiation of a knowntime-varying pattern of photon density and of a wavelength selected tobe scattered and absorbed while migrating in the subject, the inputports being placed at selected locations on the subject to probe aselected quality of the subject; and radiation pattern control meansadapted to achieve selected a time relationship of the introducedpatterns to form resulting radiation that possesses a substantialgradient in photon density as a result of the interaction of theintroduced patterns emanating from the input ports, the radiation beingscattered and absorbed in migration paths in the subject. The gradientin photon density may be achieved by encoding the introduced radiationpatterns with a selected difference in their relative amplitude,relative phase, relative frequency or relative time. The system alsoincludes a detector adapted to detect over time, at a detection portplaced at a selected location on the subject, the radiation that hasmigrated in the subject; processing means adapted to process signals ofthe detected radiation in relation to the introduced radiation to createprocessed data indicative of the influence of the subject upon thegradient of photon density; and evaluation means adapted to examine thesubject by correlating the processed data with the locations of theinput and output ports.

[0009] Preferred embodiments of this aspect of the invention includedisplacement means adapted to move synchronously all the optical inputports or move the detection ports to another location on a predeterminedgeometric pattern; at this location the examination of the subject isperformed.

[0010] According to another aspect of the invention, a spectroscopicsystem includes at least one light source adapted to introduce, atmultiple input ports, electromagnetic non-ionizing radiation of a knowntime-varying pattern of photon density and of a wavelength selected tobe scattered and absorbed while migrating in the subject, the inputports being placed at selected locations on the subject to probe aselected quality of the subject; radiation pattern control means adaptedto achieve a selected time relationship of the introduced patterns toform resulting radiation that possesses a substantial gradient in photondensity as a result of the interaction of the introduced patternsemanating from the input ports, the radiation being scattered andabsorbed in migration paths in the subject. The system also includes adetector adapted to detect over time, at a detection port placed at aselected location on the subject, the radiation that has migrated in thesubject; displacement means adapted to move the detection port tovarious locations on a predetermined geometric pattern, the variouslocations being used to detect over time radiation that has migrated inthe subject; processing means adapted to process signals of the detectedradiation in relation to the introduced radiation to create processeddata indicative of the influence of the subject upon the gradient ofphoton density; and evaluation means adapted to examine the subject bycorrelating the processed data with the locations of the input andoutput ports.

[0011] According to another aspect of the invention, a spectroscopicsystem includes at least one light source adapted to introduce, atmultiple input ports, electromagnetic non-ionizing radiation of a knowntime-varying pattern of photon density and of a wavelength selected tobe scattered and absorbed while migrating in the subject, the inputports being placed at selected locations on the subject to probe aselected quality of the subject; radiation pattern control means adaptedto achieve a selected time relationship of the introduced patterns toform resulting radiation that possesses a substantial gradient in photondensity as a result of the interaction of the introduced patternsemanating from the input ports, the radiation being scattered andabsorbed in migration paths in the subject. The system also includes atleast one detector -adapted to detect over time, at multiple detectionports placed at selected locations on the subject, the radiation thathas migrated in the subject; processing means adapted to process signalsof the detected radiation in relation to the introduced radiation tocreate processed data indicative of the influence of the subject uponthe gradient of photon density, and evaluation means adapted to examinethe subject by correlating the processed data with the locations of theinput and output ports.

[0012] Preferred embodiments of this aspect of the invention includedisplacement means adapted to move at least one of the detection portsto another location on a predetermined geometric pattern, the otherlocation being used to perform the examination of the subject.

[0013] Preferred embodiments of this aspect of the invention includerotation means adapted to rotate synchronously the optical input portswhile introducing the resulting radiation along a predeterminedgeometric pattern, the input port rotation being used to perform theexamination of a region of the subject.

[0014] Preferred embodiments of the above described aspects of theinvention are also used to locate a fluorescent constituent of interestin the subject; the wavelength of the introduced radiation is selectedto be absorbed in the fluorescent constituent, the detected radiation isemitted from the fluorescent constituent and processed to determinelocation of the fluorescent constituent.

[0015] According to another aspect of the invention, a spectroscopicsystem includes a light source adapted to introduce, at an input port,electromagnetic non-ionizing radiation of a known time-varying patternof photon density and of a wavelength selected to be scattered andabsorbed while migrating in the subject, the input port being placed ata selected location on the subject to probe a selected quality of thesubject; detectors adapted to detect over time, at multiple detectionports placed at selected locations on the subject, the radiation thathas migrated in the subject; the time relationship of the detection overtime, at the detection ports, being selected to observe a gradient inphoton density formed as a result of the interaction of the introducedradiation with the subject. The system also includes processing meansadapted to process signals of the detected radiation in relation to theintroduced radiation to create processed data indicative of theinfluence of the subject upon the gradient of photon density, andevaluation means adapted to examine the subject by correlating theprocessed data with the locations of the input and output ports.

[0016] Preferred embodiments of this aspect of the invention of theinvention include displacement means adapted to move at least one of thedetection ports to another location on a predetermined geometricpattern, the other location being used to perform the examination of thesubject.

[0017] According to another aspect of the invention, a spectroscopicsystem includes a light source adapted to introduce, at an input port,electromagnetic non-ionizing radiation of a known time-varying patternof photon density and of a wavelength selected to be scattered andabsorbed by a fluorescent constituent while migrating in the subject,the input port being placed at a selected location on the subject tolocate the fluorescent constituent of the subject; detectors adapted todetect over time, at multiple detection ports placed at selectedlocations on the subject, fluorescent radiation that has migrated in thesubject. The system also includes processing means adapted to processsignals of the detected radiation in relation-to the introducedradiation to create processed data indicative of location of thefluorescent constituent of the subject, and evaluation means adapted toexamine the subject by correlating the processed data with the locationsof the input and output ports.

[0018] Preferred embodiments of this aspect of the invention includedisplacement means adapted to move at least one of the detection portsto another location on a predetermined geometric pattern, the otherlocation being used to locate the fluorescent constituent of thesubject.

[0019] Preferred embodiments of the above-described aspects of theinvention use one or more of the following features:

[0020] The time-varying pattern comprises radiation of a selectedwavelength intensity modulated at a selected frequency. The radiationpattern control means are further adapted to control a selected phaserelationship between the modulated radiation patterns introduced fromeach of the input ports having to produce in at least one direction asteep phase change and a sharp minimum in the intensity of theradiation.

[0021] The radiation pattern control means are further adapted to imposeon all the introduced radiation patterns an identical time-varying phasecomponent thereby changing the spatial orientation of the direction ofthe steep phase change and the sharp minimum in the intensity of theradiation.

[0022] The time-varying pattern comprises radiation of a selectedwavelength intensity modulated at a selected frequency. The radiationpattern control means are further adapted to control a selectedfrequency relationship between the modulated radiation patternsintroduced from each of the input ports having to produce in at leastone direction a steep phase change and a sharp minimum in the intensityof the radiation.

[0023] The time-varying pattern comprises radiation of a selectedwavelength intensity modulated at a selected frequency. The radiationpattern control means are further adapted to control a selectedamplitude relationship between the modulated radiation patternsintroduced from each of the input ports having to produce in at leastone direction a steep phase change and a sharp minimum in the intensityof the radiation.

[0024] The radiation pattern control means are further adapted to add toall the introduced radiation patterns an identical time-varyingamplitude component thereby changing the spatial orientation of thedirection of the steep phase change and the sharp minimum in theintensity of the radiation.

[0025] The radiation is modulated at a frequency that enables resolutionof the phase shift that originates during migration of photons in thesubject.

[0026] The frequency is on the order of 10⁸ Hz.

[0027] The processing means further adapted to determine the phase orthe intensity of the radiation altered by scattering and absorption inthe subject.

[0028] The wavelength of the radiation is susceptible to changes in anendogenous or exogenous tissue pigment of the subject.

[0029] The gradient in photon density may also be achieved by encodingthe introduced radiation patterns with a selected difference in theirrelative amplitude, relative phase, relative frequency or relative time.

[0030] Other advantages and features of the invention will be apparentfrom the following description of the preferred embodiment and from theclaims.

BRIEF DESCRIPTION OF THE DRAWING

[0031]FIGS. 1, 1A and 1B show diagrammatically phase modulation imagingsystems employing several input ports and one detection port inaccordance with the present invention.

[0032]FIG. 2 is a block diagram of the phase modulation imaging systemincluding several input ports and several detection ports in accordancewith the present invention.

[0033]FIG. 2A depicts a phased array transmitter that radiates adirectional beam.

[0034]FIG. 2B depicts sequencing of the phases of an antiphasemulti-element array to achieve an electronic scan of the photon densitygradient in accordance with the present invention.

[0035]FIG. 2C depicts four element antiphased array designed for aconical scan of the photon density gradient in accordance with thepresent invention.

[0036]FIG. 2D depicts the input and output port arrangement of animaging system in accordance with the present invention.

[0037]FIGS. 3 and 3A depict an imaging system for detection of a hiddenfluorescing object in accordance with the present invention.

[0038]FIG. 4 is a block diagram of an alternative embodiment of a dualwavelength PMS system.

[0039]FIG. 4A is a schematic diagram of an oscillator circuit of FIG. 4.

[0040]FIG. 4B is a schematic diagram of a PMT heterodyne modulation andmixing network shown in FIG. 4.

[0041]FIG. 4C is a schematic diagram of an AGC circuit shown in FIG. 4.

[0042]FIG. 4D is a schematic diagram of a phase detector circuit shownin FIG. 4.

[0043]FIGS. 5A, 5B, and 5C illustrate changes in optical fieldpropagating in a strongly scattering medium which includes a stronglyabsorbing component.

[0044]FIG. 6 shows an experimental arrangement of a two element phasedarray used in an interference experiment.

[0045]FIGS. 6A, 6B, and 6C show detected interference patterns of twodiffusive waves.

[0046]FIG. 7 displays the phase shifts measured for a two element array(curve A), and for a single source (curve B).

[0047]FIG. 8A depicts an experimental arrangement of sources of a fourelement phased array and a detector.

[0048]FIGS. 8B and 8C display the intensities and the phase shiftsmeasured for the four element array of FIG. 8A, respectively.

[0049]FIG. 9A depicts an experimental arrangement of sources of a fourelement phased array, a detector, and a strongly absorbing object.

[0050]FIGS. 9B, 9C display respectively the intensities and the phaseshifts measured for the four element array of FIG. 9A scanning absorbingobjects of different sizes.

[0051]FIG. 9D displays the phase shifts measured for the four elementarray of FIG. 9A scanning absorbing objects of different absorptioncoefficients.

[0052]FIG. 10A an experimental arrangement of sources of a four elementphased array, a detector, and two strongly absorbing objects.

[0053]FIG. 10B displays the phase shifts measured for he four elementarray of FIG. 10A scanning two absorbing objects of different sizes.

[0054]FIG. 11 depict diagrammatically a single wavelength localizationsystem utilizing a conical scanner.

[0055]FIGS. 11A and 11B depict diagrammatically imaging systemsutilizing one or two dimensional phased array transmitters.

[0056]FIGS. 12A and 12B depict an imaging system comprising a twodimensional phased array transmitter and detection array.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] Imaging system embodiments of the present invention based uponinterference effects of radiation migrating in a subject havingscattering and absorptive properties are shown in FIGS. 1, 2, and 3. Thesystems effectively utilize, in this scattering medium, a directionalbeam of visible or IR radiation generated and/or detected by an array ofsources and/or detectors, respectively. For instance, in the case of anarray of sources, each source is placed at a selected location in thearray and emits intensity modulated radiation, preferably coherentradiation from a laser diode, of a selected intensity and phase. Thecriteria for selecting the source locations, the intensities, and thephases of the respective sources is the shape of the desired beam thatat any time point possesses a substantial photon density gradientproduced by interference effects of radiation from the various sources.This gradient of photon density is localized and has directionalproperties. Overall, the resulting radiation formed by interference ofthe radiation of the individual sources migrates in a selected directionin the subject. In an antiphase system, the wavefront of the beam hassections of equal photon density separated by a sharp localized changein photon density. Selected different locations of the photon densitygradient are shown in FIG. 2B.

[0058] In general, the wavefront propagates in the selected direction inthe subject and the gradient of photon density is localized in one ormore planes extending from the source array in a selected direction. Ifthe subject includes a localized object having different scattering andabsorptive properties from those of the surrounding environment, thepropagating radiated field is perturbed. This perturbation is detectedand from the source detector geometry the perturbing object can belocated.

[0059] Referring to the embodiment of FIGS. 1 and 1A, the imaging systemutilizes an array of laser diodes 12, 14, 16, and 18 for introducinglight into the tissue at selected locations. The geometry of opticalinput ports 11, 13, 15, 17 and of an optical output port 19 is selectedto examine a specific part of the tissue. From the known geometry of theoptical input ports and the detection port and from the shape of theintroduced and detected radiation, a computer can locate a hidden object9 of examined tissue 8 (for example, a head or breast). A masteroscillator 22, which operates at 200 MHz, excites laser diodes 12through 18, that emit light of a selected wavelength (e.g., 760 nm). Thelight from each laser diode is conducted to the respective input portplaced on a subject via a set optical fibers , A detector 24 detects thelight that has migrated through the examined tissue. Preferably,detector 24 includes a photomultiplier tube (e.g., Hamamatsu R928)powered by a high voltage supply which outputs about 900 V in order toensure a high gain. A local oscillator 26 operating at a convenientoffset frequency (e.g., 25 kHz) sends a signal to a mixer 28 and areference signal to detector 24. Accordingly, an output waveform 25 fromdetector 24 is at a carrier frequency equal to the difference of thedetected and reference frequency, i.e., 25 kHz.

[0060] Detector 24 (for example, PMT Hamamatsu R928 or Hamamatsu R1645u)detects the scattered and absorbed light that has migrated through thesubject. Detection port 19 is located several centimeters from thelocation of the input ports. The PMT detector is connected to thesubject by the fiber optic guide, or, alternatively, may be directlyplaced on the subject. It has been found that the most cost-effectivedetector for measuring signals of frequencies on the order of 10⁸ Hz isHamamatsu R928. However, the Hamamatsu R1645u detector is preferred dueto its high precision. The second dynode of the PMT of detector 24 ismodulated by 200.025 MHz signal 27 so that the 25 kHz hetrodyned signal25 is received by a phase detector 30. Phase detector 30 also receivesreference signal 29 from mixer 28. If phase detector 30 is a lock-inamplifier then the output signals are the phase shift and the intensityof the detected signal. Both the phase shift and the intensity of thedetected light characterize the migration path of photons in the subject(e.g., the brain tissue).

[0061] Alternatively, a tunable dye laser or other laser sourceconnected to a wide band acousto-optical modulator operating at thecarrier frequency, e.g., 200 MHz can be used instead of the laser diode.The acousto-optical modulator modulates the intensity of the lightemitted by the laser at the selected carrier frequency.

[0062] The invention also envisions using only one source of coherentlight that irradiates one end of several optical fibers at the sametime. The other end of each fiber is placed on the subject at a selectedinput port location. This source radiates light of a selected timevarying pattern. The phase relationship and the intensity of the lightcarried by each fiber is varied by creating a time delay (e.g.,different fiber length) and by coupling different amounts of light intoeach fiber.

[0063]FIG. 1B shows diagrammatically an imaging system of FIG. 1 furtheradapted to encode the transmitted light sing an offset frequency.Oscillators 22 a, 22 b, 22 c and 22 d drive four laser diodes atfrequencies 30.025 MHz, 30.035 MHz, 30.045 MHz and 30.055 MHz,respectively. The laser diodes introduce the light that migrates intissue 8 and is collected at detection port 19 and detected by PMTdetector 24. Local oscillator 26 provides a 30 MHz reference signal todetector 24 that outputs a detection signal having 25 kHz, 35 kHz, 45kHz and 55 kHz frequency components. Each component signal is phasedetected at a corresponding phase detector (30 a, 30 b, 30 c and 30 d)having a suitable frequency filter. The phase detectors provide a phaseshift, migration pathlength and amplitude for each frequency.

[0064] The imaging systems of FIGS. 1, 2, and 3 are shown to have alight source of a single wavelength; however, a dual wavelength imagingsystem is also envisioned according to this invention. In the dualwavelength imaging system two laser diodes or a tunable wavelength lasergenerate light of two wavelengths that is coupled to an optical fiber.Such a system will now be described.

[0065] A dual wavelength operation is shown in FIG. 4. The systemincludes a master oscillator 60 operating at 200 MHz and an oscillator62 operating at 200.025 MHz which is offset 25 kHz from the masteroscillator frequency. The offset frequency of 25 kHz is a convenientfrequency for phase detection in this system; however, other offsetfrequencies as high as a few megahertz can be used. Oscillator 60alternatively drives two sets of laser diodes 64 a, 64 b, . . . , 64 nand 66 a, 66 b, . . . , 66 n using switches 61 a, 61 b, . . . , 66 n.These switches are driven electronically to couple a selected wavelengthinto the optical fiber and also to achieve a selected radiation patternresulting from the radiation emanating from the individual fibers. Anoutput 8 mm fiber coupler 72 collects photons for an R928 PMT detector74. The second dynode (shown in FIG. 3B) of PMT 74 is modulated with a200.025 MHz reference signal generated by oscillator 62 and amplified byan amplifier 63. Thus, the output signal of the PMT detector has afrequency of 25 kHz. PMT detector 74 alternately detects light of thetwo laser diodes that has migrated in the tissue and producescorresponding output signals, which are filtered by a filter 76 andleveled by an automatic gain control (AGC) circuit 79. A referencesignal of 25 kHz is produced in a mixer 65 by mixing the 200 and 200.025MHz oscillator signals. The reference 25 kHz signal is also leveledusing the second AGC 77 and fed into a phase detector 79. Phase detector79 generates a signal indicative of the phase of each output signalrelative to the phase of the reference signal. The outputs of phasedetector 79 are alternately selected by an electronic switch 80,filtered, and then input to an adder 82 and a subtractor 81 to producesum and difference signals proportional to <L>_(λ1)+<L>_(λ2) and<L>_(λ1)−<L>_(λ2). The difference and sum signals are then used tocalculate changes in the probed pigment and in the blood volume,respectively.

[0066] A schematic diagram of preferred oscillator 60 or 62 is shown inFIG. 4A. This circuit has a drift of only 0.03 degrees/hr. (Weng, etal., “Measurement of Biological Tissue Metabolism Using Phase ModulationSpectroscopic Measurement,” SPIE, Vol. 143, p. 161, 1991, which isincorporated herein by reference). The crystal is neutralized, whichenables operation at resonance, and thus achieves long-term stability.The respective crystals of oscillators 60 and 62 are offset from eachother by 25 kHz. This circuit provides a sufficient output to directlydrive a 5 mW laser diode.

[0067] A modulation circuit 75 for the second dynode of the PMT is shownin FIG. 4B. This circuit -uses a resonant circuit 75 a with an impedanceof 20,000 ohms instead of the usual 50 Ω load with very high powerdissipation, providing a 50 V drive of the photomultiplier dynode whiledissipating only a few watts of power.

[0068] To obtain stable operation of the phase detector, a stable inputsignal is required. The 25 kHz AGC circuit 77, 78 illustrated in FIG. 4Cincludes an MC 1350 integrated circuit U1, featuring wide range AGC foruse as an amplifier. The signal amplitude is controlled by a feedbacknetwork, as shown. A major reason for the accurate detection of phasechanges by the PMT system is that the phase detector input signal levelis kept nearly constant by the AGC circuit. Since the input voltagechange of between 2 and 6 volts causes variation in the phase shift ofonly 0.2%, the AGC circuit eliminates the need for a very stable highvoltage power supply.

[0069] A preferred phase detector circuit is shown in FIG. 4D. Twosinusoidal signals (the measurement signal and the reference signal) aretransformed to a square wave signal by a Schmitt trigger circuit 79 a.The phase of the square wave signal is shifted by an RC change (composedof R11, R12, C8), which makes it possible to change the measuring range.The detector further includes a 74HC221 integrated circuit. The lock-inamplifier technique obtained to derive the difference of the phase andamplitude of the two signals has the highest signal to noise ratiopossible for this type of equipment.

[0070] The above-described systems utilize the carrier frequency on theorder of 10⁸ Hz which is sufficiently fast to resolve the phase shift ofthe detected light. The characteristic time, the time it takes for aphoton to migrate between an input port and an output port, is severalnanoseconds. The sensitivity of the system is high, approximately 70°per nanosecond or 3° per centimeter change of pathlength, as observed inexperimental models. Selection of the modulation frequency also dependson the desired penetration depth and resolution of the imaging systemthat will be described below. If deep penetration is desired, a lowmodulation frequency (e.g., 40 MHz) is selected, and if shallowpenetration is needed, modulation frequencies as high as 10⁹ Hz can beused.

[0071] Referring to FIGS. 1 and 1A, a master oscillator 22 operates at amodulation frequency in the range of 40 to 400 MHz selected according tothe desired penetration depth of the optical field. The array of laserdiodes 12, 14, 16, and 18 generates a highly directional radiationpattern, which is employed in the tissue examination.

[0072] In one preferred mode of operation, laser diodes 12 to 18 operatein a phased array pattern which is introduced into the tissue anddetected by a single PMT detector 30. Master oscillator 22 operating at200 MHz drives a multi-channel phased splitter which gives outputs atpredetermined phases. Input ports 11 through 17 are located at selecteddistances and an appropriate phasing of the array creates a directionalbeam and enables scanning of the optical field in two dimensions acrossthe tissue, as shown in FIGS. 2A, 2B, and 2D. After migrating throughthe tissue, the optical field is collected in a large area fiber onselected locations 19. The detected signals are heterodyned in the PMTdetector 24 by utilizing the output of local oscillator 26, operating ata 25 kHz offset frequency, to detector 24. The resulting 25 kHz signalis phase detected with respect to the output signal 29 of mixer 28 anddetector 24. Phase detector 30 outputs the phase and the intensity ofsignal 25. The detected phase shifts and intensities are stored and usedfor construction of an image of the subject. This is performed bycomputer control 34, which governs the operation of the system.

[0073]FIG. 2 depicts a phase modulation imaging system comprising aninput port array for introducing radiation and a detection port arrayfor detecting radiation that has migrated in the subject. The operationof the system is controlled by computer control 34, which coordinates aTransmitter unit 32 with a receiver unit 42. Transmitter unit 32comprises several sources of visible or IR radiation adapted tointroduce a selected time-varying pattern of photon density into subject8 by array of input ports 31, 33, 35, and 37. Receiver unit 42 detectsradiation that has migrated in the subject from the input port array toan array of detectors 39, 41, 42, and 47.

[0074] The radiation sources of transmitter unit 32 are intensitymodulated at a frequency in the range of 40 MHz to 200 MHz, as describedfor the imaging system of FIG. 1. Receiver unit 42 detects and processesthe radiation using the same principles of the phase and amplitudedetection as described above. The signal detected at individual portscan be phased using appropriate delays.

[0075] Several modes of operation of the transmitter array and receiverarray are described in FIGS. 2A, 2B, 2C, and 2D. Referring to FIG. 2A,it has been known, that for a simple horizontal linear array of Nidentical elements radiating amplitude modulated light spaced adistance, d, apart. The radiating wavefront is created by theinterference effect. If all elements radiate in phase the wavefrontpropagates in a direction perpendicular to the array. However, byappropriately phasing the radiating elements, the resulting beam canscan space in two dimensions. We consider the phases of the signal alongthe plane A-A whose normal makes an angle θ₀ with respect to the arraynormal. The phase of the signal from the first radiator lags the phaseof the second radiator by a phase angle (2π/λ)d sin θ₀ because thesignal from the second radiator has to travel a distance d sin θ₀ longerthan the signal from the first radiator to reach plane A-A. Similarly,the phase of the signal from the n^(th) radiator leads that from thefirst radiator by an angle n(2π/λ))d sin θ₀. Thus, the signals from thevarious radiators can be adjusted to be in-phase along the A-A plane, ifthe phase of each radiator is increased by (2π/λ)d sin θ₀. Consequently,at a point on the wavefront in the far field of the transmitter arraythe signals from the N radiators will add up in phase, i.e., theintensity of the total normalized signal is a sum of the signals fromthe individual sources. The constructed pattern has a well defineddirectional characteristic and a well pronounced angular dependence,i.e., the transmitter pattern has a well defined transfer characteristicof the transmitter with respect to the angle θ₀.

[0076]FIG. 2B depicts an arrangement of phases for the sources thesystem of FIG. 2 operating in one preferred mode of operation. The arrayof five sources is divided into two or more portions that are phased180° apart. Each portion has at least one source. The sources of eachportion radiate amplitude modulated light of equal intensity and arespaced so that the resulting beam of two or more equally phased sourceshas a substantially flat wavefront, i.e., no gradient of photon density.on the other hand, there is a sharp 180° phase transition, a largegradient in photon density between two antiphased portions of the array.Thus, the radiated field possesses an amplitude null and a phasetransition of 180° (i.e. crossover phase), which is due to the largegradient of photon density.

[0077] Electronic scanning is performed by appropriately varying theapportionment of 0° and 180° phases on the sources. The five elementarray of FIG. 2B can have the 180° phase transition along four differentparallel planes extending from the array. Scanning is achieved byelectronically switching the sources by 180°, so that the photon densitygradient moves in the direction parallel to the location of the sources.

[0078] Using the principles described in FIGS. 2A and 2B, a conical scanof a directional beam possessing at least one substantial photon densitygradient can be accomplished using a four element antiphased array, asshown in FIG. 2C. The laser diodes are antiphased using a push pulltransformer. The phasing and amplitude of four laser diodes S₁, S₂, S₃,and S₄ arranged into a two dimensional array is modified sequentiallyusing the switches Sw₁, Sw₂, Sw₃, and Sw₆ and inductances L₁, L₂, L₃,and L₄.

[0079]FIG. 2D shows a possible arrangement of the transmitter array andthe receiver array. The above described directional beam enters subject8 at the transmitter array location and is pointed to hidden absorber 9which perturbs the migrating beam. The field perturbation is measured bythe receiver array. Scanning of the transmitter array or the receiverarray is envisioned by the present invention.

[0080] A hidden absorber that includes a fluorescent constituent isdetected using a selected excitation wavelength of the laser sources ofthe transmitter array. Then, the radiation is absorbed, and almostinstantly a fluorescent radiation of a different wavelength isre-emitted. The re-emitted radiation propagating in all directions isdetected by the receiver array.

[0081]FIG. 3 depicts a phase modulation imaging system comprising oneinput port and several arrays of detection ports. This system operatescomparably to the systems of FIGS. 1 and 2. The 754 nm light of a laserdiode 48 is amplitude modulated using master oscillator 22. The light iscoupled to subject 8 using an input port 49. The amplitude modulatedlight migrates in the subject and is scattered from hidden object 9. Itis also expected that hidden object 9 has a different effective index ofrefraction than subject 8. The migrating radiation is governed by thelaws of diffusional wave optics that are described below. The scatteredradiation migrates in several directions and is detected by detectionsystems 50, 52, and 54.

[0082] Ports 51, 53, and 55 of the detection systems can include eitherlarge area fibers or arrays of detection ports. If large area fibers areused then detector systems 50, 52, and 54 correspond to detector 24 ofFIG. 1. If arrays detection ports are used, then each of detectorsystems 50, 52, and 54 includes several individual PMT detectors. ThePMT detectors of each detector system are phased utilizing a selectedphase mode, as described above. The phasing is controlled by thecomputer control. The detected signals are heterodyned at the PMTdetectors and sent to a phase detector 58. Phase detector 58 detectsalternatively the heterodyned signals using a switch 56. Operation ofphase detector 58 is similar to the operation of phase detector 30 ofFIG. 1. The detected phase and amplitude are alternatively sent to thecomputer control using a switch 56 a. Even thought only one phasedetector is shown in FIG. 3, the invention envisions use of severalphase detectors.

[0083] If hidden absorber 9 includes a fluorescent constituent, laserdiode 48 is selected to introduce an excitation wavelength (e.g., 754nm). The introduced, intensity modulated radiation, excites thefluorescent constituent which re-emits radiation in all directions, asshown in FIG. 3. The re-emitted radiation is detected using detectorsystems 50, 52, and 54. To increase the system resolution, each detectorcan be furnished with an interference filter selected to pass only thefluorescent radiation.

[0084]FIG. 3A shows diagrammatically an imaging system used fordetection of a fluorescing object 9. The system is a modified version ofthe system of FIG. 3 wherein a four element phase array 47 introduces a200 MHz light of a 0° and 180° phase. The diffusion wave emitted fromarray 47 is re-emitted by object 9 and detected by ports 51, 53 and 55and processed as described in connection with FIG. 3. Array 47effectively codes the illumination light. Thus, when array 47 is rotatedabout the examined organ with object 9, the receivers will containinformation corresponding to the orientation of the object. Eachdetection port also includes a filter that passes only the fluorescentradiation; this improves the resolution of the system.

[0085] The interference of several waves, as described in FIG. 2A, hasbeen long known in a non-scattering medium, wherein the radiationpropagates on a straight line, but not in a strongly scattering medium.Referring to FIGS. 6, 6A, 6B, and 6C, in a simple experiment,interference of two different diffusive waves in a strongly scatteringmedium was demonstrated. Propagation of visible IR radiation in ascattering medium such as tissue can be described by diffusion ofphotons, and thus we describe it as a diffusive wave that exhibitrefraction, diffraction and interference. The diffusive waves, which canbe visualized as “ripples of brightness,” represent a scalar,over-damped traveling waves of light energy density.

[0086] Referring to FIG. 6, the two laser-diodes were separated at adistance of 4 cm and 1.2 cm from the detection port. The intensity ,modulated light of the two laser diodes at frequency 200-Hz was sentthrough two optical fibers to a container with an Intralipid™suspension. The source detector distance was varied by moving theoptical port of the detection fiber along a line parallel to theposition of the sources. FIGS. 6A, 6B, and 6C show measured maxima andminima of the optical field migrating in the medium. This datademonstrates interference between two diffusive waves created by twocoherent emitting sources of phase difference 180 degrees. FIG. 7summarizes the experiment, wherein the displacement of the detector isplotted against the phase shift measured by the detector. The phaseshift displays the steepest part of the trace, curve A, (slope of about360°/cm) at the displacement of about 2.25 cm. Curve B is measured withan optical field of source S₂. Here, the measured slope is about 30°/cm.When comparing curves A and B we demonstrate much higher sensitivity ofthe null detection of the two element array contrasted with a diminishedsensitivity to the detector displacement when using a single sourcearrangement. The sensitivity of the two source arrangement is increasedby about a factor of 10. The sensitivity is further increased when usingfour or more element phased array, which sharpens the photon densitygradient and thus provides a higher resolution for locating the hiddenobject. P In a strongly scattering medium, the emitted photons undergo alarge number of collisions and their migration can be determined byapplying the diffusion equation. The diffusion equation for photons in auniformly scattering medium was solved by E. Gratton et al., “Thepossibility of a near infrared optical imaging system using frequencydomain methods.” in Mind Brian Imaging Program, Japan 1990; and by J.Fishkin et al., “Diffusion of intensity modulated near-infrared light inturbid media”, SPIE Vol. 1413 (1991) p. 122. A solution of the diffusionequation was obtained for the light of a point source (at r=0) radiatingS{1+M exp[−i (ωt+e)]} photons, wherein S is the source strength(photons/sec.), M is the modulation of the source at frequency ω, and eis an arbitrary phase. The photon intensity can be calculated as

I( r,t)=c*ρ( r,t),

[0087] wherein ρ(r,t) is the photon density and c=10⁸ m/s is thevelocity of light.

[0088] When solving the diffusion equation using a spherical-harmonicsapproximation in a non-absorbing medium for the density of photons ρ (r,t) than

I( r,t)=(I ₀ /Dr )+(I ₀ /Dr )exp [−r(ω/2cD)^(½)]×exp[ir (ω/2cD)^(½)−i(ωt+e) ],

[0089] wherein the diffusion constant D is ½ of the mean free path. Inthe absence of an amplitude modulated signal (ω=0) the solutioncorresponds to a spherical wave propagating without attenuation. For anon-zero frequency, the amplitude of the signal at a frequency ωdecreases exponentially. The light wave front the emitted advances atthe constant velocity V

V=(2Dcω)^(½)

[0090] and has wavelength

λ=2 π(2cD/ω)^(½)

[0091] The above equations show that higher modulation frequencies yieldshorter effective wavelengths, and smaller diffusion constants also giveshorter effective wavelengths. In principle, short wavelengths can beobtained using high frequency modulated waves in a very turbid medium.However, the amplitude of the modulated wave decreases exponentiallywith the modulation frequency. Therefore, the best resolution, i.e., theshortest wavelength, is obtained using the highest frequency which stillgives a measurable signal. The diffusion process limits the penetrationdepth at any given modulation frequency, because of the exponentialdecrease of the wave's amplitude, and also decreases the velocity oflight propagation.

[0092] The above described diffusion wave approach treats amplitudemodulated light waves in scattering media using the framework of waveoptics. The photon intensity, calculated as superposition of differentwaves, constitutes a scalar field, propagating at a constant velocity.At any given modulation frequency, the wave optics phenomenology ofscalar fields is valid. Therefore, in the frequency-domain, themeasurement and analysis of light diffusing in tissues from severalsources will undergo constructive and destructive interference.Furthermore, wave refraction occurs at a boundary between two differenttissues. It causes a deviation of the direction of propagation of thewave front, and thus there is a change in the amplitude and phase shiftof the propagation wave. The direction change is a function of the ratioof the effective index of refraction in the two tissues. In diffusionalwave optics, on the other hand, the wave's amplitude is exponentiallyattenuated as the wave propagates in the scattering medium. Thisattenuation is in addition to the exponential attenuation caused byfinite absorption of the medium.

[0093] Amplitude modulated waves propagate coherently in the scatteringmedium; this is crucial for image reconstruction. It is possible toaccurately measure in real time, the average intensity, amplitude, andphase of the wave front over a large area using a single detector or anarray of detectors applying well-established frequency-domain methods.

[0094] The emitters are varied sequentially in phase starting with thefirst emitter in the line and followed by subsequent emitters. Eachemitter emits a spherical wave and propagation of the resultant beam isperpendicular to the wavefront. If all the transmitter delays are equal,the beam travels straight ahead. Delay lines which produce variabletransmitter delays can be used to obtain appropriate phasing forsteering the beam across the tissue. The same principle can apply duringreception.

[0095] There are two important aspects of imaging as envisioned by thepresent invention. The first is a geometrical aspect and the second isphasing of the transmitters and receivers.

[0096] It is also possible to construct a two-dimensional array fortwo-dimensional pointing (e.g., FIG. 2C). The multiplexing switches usedwith these arrays can be constructed as an integral part of the arrayand can consist of field effect transistors arranged so that access toany element may be obtained by the application of two adverse signals.

[0097] In addition to electronic scanning, the two-dimensional scanningcan be achieved by moving the array of sources and detectors in aregular pre-determined pattern in a plane parallel to that beinginvestigated in the subject. For maximum detection, the detector isplaces in the plane of the photon density gradient of the resultingfield created by the array of sources. The plane of the photon densitygradient is swept as the array moves. In this sweeping action, as astrongly or weakly absorbing object enters the radiation field, thedetector registers a field imbalance due to the above describedrefraction of the propagating radiation. A two-dimensional image isformed by storing the information while the probe is moved across thesubject. Several scans in different imaging planes are envisioned by theinvention. If the system is duplicated or time shared in two other facesof a cube, an algorithm would be used to provide a 3-dimensional pictureof the object by triangulation. For a linear array of sources, there isa plane in which the null is sensitively detected, and the intersectionof three planes (particularly at orthogonal intersection) defines thelocation of a hidden absorber. The data storage is accomplishedelectronically.

[0098] The detector detects the intensity and the phase shift of theradiation that has migrated in the subject. The phase shift depends onthe tissue properties, i.e., absorption and scattering. For the lowfrequencies the phase shift is proportional to ((1−g)μ_(s)/μ_(a))^(½)and for the high frequencies proportional to 1/μ_(a). To obtain desiredpenetration depth, appropriate frequency for both master oscillator 22and local oscillator 26 is chosen; however, the phase relationship ofthe laser diodes is maintained.

[0099] Different types of phased arrays are designed for optimalexamination and imaging of different human organs (e.g., human head orbreast). For example, a mosaic of optical input ports and opticaldetection ports defined by positions of optical fibers attached to askull cap may be used. A standardized mapping may be developed alsousing x-ray techniques. Contrast labeling of different physiologicalstructures will aid the visualization and orientation. The amplitude andphase of the signals can be monitored on a precision oscilloscope. Inorder to scan the phased array past a fixed object of approximatelyknown position, as in needle localization procedures, the location ofthe input and output ports will be scanned past the object and theposition of maximum phase shift will be recorded in one-dimension;however, detection in two and three dimension can be performed in thesame way.

[0100] In the preferred mode of operation, the array of sources isphased 180° apart, as shown in FIG. 8A. There is a sharp 180° transitionof photon density wave, a large gradient in photon density, from S₂, S₂sources to the S₃, S₄ sources. Thus, the radiated field gives anamplitude null and a phase transition of 180° corresponding to the y-zplane, i.e., perpendicular to the detector. If a larger number ofsimilarly phased sources is used, the transitions are even sharper. Thearray produces a uniform photon density pattern on each side of thearray, as shown in FIGS. 8B and 8C. If an absorbing object is placed inthis directional field of diffusing optical waves, imbalance in thephoton density is measured. The detection of a hidden object isaccomplished by translating the experimental transmitter-receiver systemof FIG. 8A.

[0101] In addition to the mechanical scanning achieved by moving of theinput-output port system, electronic scanning can be performed using themultiple source and multiple detector system of FIG. 2. As shown in FIG.2B for an array of five sources, there is a 180° phase transition in theresulting migrating field due to the 180° phase difference between theantiphased sources radiating amplitude modulated light. The plane of the180° phase transition can be shifted in parallel by appropriatelyvarying the apportionment of 0° and 180° phases on the sources. This isperformed by sequentially switching the phase of the sources by 180°. Ineach case, the detection port located on this plane is used forcollecting the data. As the sources are electronically switched by 180°,the detection array can be also electronically switched from onedetection port to another. The signal from the receiving optical fiberis coupled to one shared PMT detector. However, the system can alsoinclude several detectors. If the systems of FIGS. 1 or 1A are used, theelectronic source scanning can be combined with synchronous mechanicalmovement of the detection port.

[0102] In general, the invention utilizes the photon density gradientcreated in the migrating field since it increases the resolution of thedetection. As known to one skilled in the art, the photon densitygradient formed by interference effects of introduced waves can becreated not only by appropriate phasing of the sources but also by othermethods such as appropriately spacing the sources, creating an imbalancein the radiated intensity of the individual sources, and other. Theimbalance may be achieved by modulating the amplitude of one source withrespect to another; this displaces the null in the correspondingdirection. Furthermore, the introduced signal can be encoded by thefrequency or a selected phase.

[0103]FIG. 8A shows the arrangement of the input ports 11 to 17 anddetection port 19 of FIG. 1. As described above, light of each laserdiode 12 through 18 is intensity modulated at the 200 Mz frequency.Wavelength of the intensity modulated radiation is$\lambda = \left( \frac{4\pi \quad {c/n}}{3f\quad \mu_{s}} \right)^{\frac{1}{2}}$

[0104] wherein f is the modulation frequency of 200 MHz, μ^(s)is thescattering factor which is approximately 10 cm⁻¹ in an Intralipidsolution with refractive index n, and c is 3×10 ⁸ cm/s. Thus, theexpected wavelength is about 7 cm. The input ports S₁, S₂, S₃, and S₄are set 3.5 cm apart and are anti-phased by 180° using a push pulltransformer. The antiphased array creates a large gradient in photondensity chosen to take advantage of the destructive interference withthe null detection. The laser diodes emitting 754 nm light are intensitymodulated at 200 MHz using master oscillator 22, and the localoscillator 26 is operating at 200.025 MHz to perform the dynodemodulation of PMT detector 24. The detected intensities and phase shiftsof an x-direction scan (FIG. 8A) of detection port 19 are plotted inFIGS. 8B and 8C, respectively. As expected , the intensity has a sharpminimum in between sources S₂ and S₃ where the phase is changed 180°.The peak width at half maximum is about 2 cm. In addition to thex-direction scan of the detection port, the detection port was scannedin y-direction wherein, as expected, no variation was observed.

[0105] Referring to FIG. 9A, cylindrical objects of different diameter,d, were scanned using the previously described phased array. The objectswere placed in the middle of the linear array displaced 2.5 cm from thex-axis. The detection port was located on the x-axis and each object wasmoved parallel to the x-axis at the 2.5 cm y displacement. The intensityand phase shift detected at different locations are plotted in FIGS. 9Band 9C, respectively. The intensity pattern for each moving object hastwo maximum and one minimum when the scanned object was located at x=0,y=2.5 point during its scan along the x-axis. At this point, a largephase change is detected, as shown in FIG. 9C. The phase detection hasinherently larger resolution of a localized absorber; a hidden object ofsize as small as 0.8 mm can be detected.

[0106] The response due to different absorption of the hidden object wasstudied using a 5 mm cylinder of different absorption coefficientscanned by the 4 element phased array of FIG. 9A. The detected phasechange is shown in FIG. 9D. The 5 mm black rod displays the largestphase change due to its high absorption, and the cylinder filled withcardiogreen 3.5 mg/l which has absorption coefficient μ_(a)=200 cm¹shows the smallest phase change. In scanning of a hidden object, theseexperiments correspond to mechanically displacing the source detectorsystem, or electronically scanning the subject.

[0107] Scanning of two objects of a different diameter is shown in FIG.10A. Two cylinders of different diameter are scanned across the fourelement phased array located on the x-axis. The detection port inlocated at y=5 cm. In FIG. 10B the detected phase change in plottedagainst the displacement of these objects. Curve A represents the phasechange of two cylinders of diameters 5 mm and 10 mm separated 3 cmapart. Curve B was measured using 16 mm cylinder instead the 5 mmcylinder. In this case, wherein the two cylinder separation is smaller,the phase detector can not resolve the two objects.

[0108] The imaging resolution is increased by increasing the number ofelements of the phased array, since the main lobe of the resultant beambecomes much sharper, the gradient of photon density is larger. Phasedarrays of different number of elements and different shapes are used forimaging different organs. For example, in tumor imaging, the fourelement phased array of FIG. 8A having an approximately linear shape canbe used for imaging of the brain. On the other hand, a rectangular or acircular phased array would be used for imaging of a hidden tumor in thebreast. The modulation frequency and the element spacing is adjusted toobtain proper focussing in each case.

[0109] In general, an imaging system will operate using the followingmodes of operation that arise from the above-described principles. Inthe first mode of operation, a series of zero phased, appropriatelyspaced sources create photon diffusion waves. One or more detectorssensitive to a selected wavelength detect the phase and the amplitude ofthe migrating wave. Individual sources and detectors may be coded andactivated according to selected detection and display schemes. Thesecond mode of operation uses a series of sources phased at 0° and 180°(or any other offset phase that gives adequate sensitivity) with respectto each other. The detector set at the null point of the array detectschanges in the phase at the null point. Each detector may use aninterference filter to limit its sensitivity to a selected wavelength.The third mode of operation may further complement the second mode bynot only detecting the phase transition but also the amplitude null. Themost sensitive detection is achieved when a hidden object is located inthe midline plane of the 0-180° signal. An object is located using bothsignals and their appropriate integrals or derivatives are used toenhance the resolution of the system. The display will also utilizeinformation from several wavelengths, for example, when 750 nm and 850nm sources are used, the signal difference provides information aboutthe hemoglobin oxygenation and the sum about the blood concentration.Other wavelengths sensitive to endogenous or exogenous tissue pigmentsmay be used. The same source array may be designed to operate in allthree modes of operation. A computer supervisory system selects asuitable mode of operation for optimal sensitivity.

[0110] Referring to FIG. 11, a single wavelength localization system 83employs a conical scanner 85 that introduces optical radiation of aselected wavelength from four laser sources 87 to tissue 8. Therelationship of the introduced patters is selected so that the resultingintroduced radiation pattern forms a cone scanning in the examinationspace. The operation principles of array 87 were described in connectionwith FIGS. 2A, 2B and 2C. Oscillator 62 generates a 200.025 MHz drivesignal 91 that is introduced to modulators 90 a and 90 b. Furthermore,the phase of the drive signal is shifted by 90° in modulator 90 arelative to the phase of the drive signal is modulator 90 b, and thephase signals are varied over time at 60 Hz. Each of the quadraturephase signals (92, 93) are splitted in splitter 89 a and 89 b to from anin-phase and anti-phase drive signals. The four drive signals drive fourlaser diodes labeled N, S, W and E of array 87. Thus array 87 generatesa scanning conical signal (88) that includes a sharp phase change in thecenter of the signal cone. Array 87 has four 780 nm laser diodes, butother wavelengths selected for a high sensitivity to a tissue componentmay be employed. Furthermore a multi-wavelength array can also be used.

[0111] The introduced diffusive photon density wave migrates in tissue 8and is detected at optical port 86 of an optical fiber connected to PMTdetector 75. As described above, the detected radiation is heterodynedusing a 200 MHz reference signal and the corresponding 25 kHz signal iscoupled to amplitude detector 96 and phase detector 79. Phase detector79 measures the phase shift between the introduced and detectedradiation patterns. The output of the phase detector is correlated withthe 60 Hz signals 92 and 93 to produce localization signalscorresponding to the N, S, W and E laser sources. The localizationsignals may be monitored using an oscilloscope.

[0112] When port 86 is symmetrically arranged in respect to the locationof the radiation cone 88 and there is no field perturbation (i.e., nohidden object 9), the oscilloscope will display a circular pattern. Inthe same arrangement of cone 88 and port 86, if hidden object 9 islocated in the radiation field, the oscilloscope pattern will no longerbe symmetrical, e.g., the circular pattern may change to an ellipticalpattern. For maximum sensitivity, detection port 86 mechanically scansaround tissue 8 and is locked onto the scanning conical signal so thatport 86 always points to the center of cone 88, i.e., port 86 is in thenull location.

[0113] Referring to FIG. 11A, a phase modulation imaging system 100includes a two-dimensional phased array transmitter 102 connected tolaser sources 104. Electronics 120 drives laser sources 104 and alsoprovides reference signals to the detection system. Optical detector 150includes an optical input port 152 defined by a relatively large areaoptical fiber 154 connected to a PMT detector 156.

[0114] Phased array transmitter 102 includes a horizontal array 106 anda vertical array 112 of input ports connected by a set of optical fibers(not shown in FIG. 11) to laser sources 104 that include 754 nm and 816nm laser diodes labeled a and b, respectively. Diodes 107, 108, 109, and110 of the horizontal array 106 are driven by a push-pull transformer122, and diodes 103, 114, 115, and 116 of the vertical array 112 aredriven by a push-pull transformer 124. The resolution of the system maybe increased by adding more sources.

[0115] The horizontal sources are intensity modulated at a frequency ofapproximately 200.025 MHz generated by 200.025 MHz oscillator 124 and ahorizontal TV scan drive 128 generating a saw-tooth signal of 60 Hz. Ahorizontal reference signal 127 of 25 kHz supplied to phase detector 162is produced in a mixer 126 by mixing the 200.025 MHz signal fromoscillator 124 and a 200 MHz signal from oscillator 121. The verticalsources are intensity modulated at a frequency of approximately 200.2MHz generated by a 200.2 MHz oscillator 134 and a vertical TV scan drive138 generating a saw-tooth signal 139 of 1 kHz. A vertical referencesignal 137 of 200 kHz supplied to phase detector 164 is produced in amixer 136 by mixing the 200.2 MHz signal from oscillator 134 and the 200MHz from oscillator 121.

[0116] The emitted light of either 754 nm or 816 nm, alternated at 60 Hzby a chopper, migrates in the examined tissue as described above and isdetected at input port 152. The detected light is heterodyned at PMTdetector 156 receiving a reference 200 MHz signal from oscillator 121.The detector signal is then filtered at 25 kHz and 200 kHz using filters158 and 160, respectively. Phase detectors 162 and 164, receiving 25 kHzand 200 kHz reference signals, respectively, determine at each frequencythe phase shift of the detected light in respect to the introducedlight.

[0117] As described above, the phase shift and the related opticalpathlength of the migrating photons directly reflect the tissueproperties. System 100 can distinguish the differences in the phaseshift of the light emitted from horizontal array 106 and vertical array112 since the emitted light from each array is modulated at slightlydifferent frequency.

[0118] Transmitter array 102 is designed to reflect the geometry of theexamined tissue and a possible location of hidden objects. The hiddenobjects A, B, and C of FIG. 11 targeted by array 102 are 3 to 4 cm inthe scattering medium. Thus, array 102 has the input ports spacedapproximately 1 cm apart and equidistantly from the center. Detectionport 152 is located about 7 to 10 cm from transmitter 102 and may bemechanically scanned in correlation with the total introduced field ofarray 102.

[0119] PMT detector 156 receives signals from the horizontal andvertical arrays. The modulation offset vertical frequency of thewaveform is about 10 times higher than for the horizontal waveform sincethe repeatability of the vertical scan is higher than the repeatabilityof the horizontal scan. Approximately the same frequency difference isused for the horizontal and vertical TV scans. The output from phasedetectors 162 or 164 represents the phase value as detected along thehorizontal axis and the vertical axis. A localized absorbing orscattering object (e.g., a tumor, localized bleeding) will cause a“resonance curve” type response. The detected phase shifts for eachsignal is differentiated (166 and 168) to “sharpen” the chances andincrease the resolution. The horizontal and vertical outputs are addedin a summing amplifier 170 and are coupled to a video input of a 500line TV display 180. The display may be graded in a gray scale or afalse color scale. The resolution achieved in the above describedone-dimensional experiments can be further improved and thesignal-to-noise ratio enhanced by employing a computer storage of thescanned data and integrating over a number of scans and using contrastenhancing algorithms. Alteratively, a “slow scan” TV may be used withnarrow banding of the outputs of the phase detectors.

[0120] System 100 may also include an amplitude detector 157 thatdetects the amplitude of the detected radiation at the 25 kHz and 200kHz frequencies. The detected amplitude signals are manipulated the sameway as the phase shift signals and fed to display 180. The use of boththe amplitude signals and the phase signals improves resolution of theimage.

[0121]FIG. 11B shows diagrammatically a low frequency imaging system 190that employs techniques similar to the ones used in system 100 of FIG.11A. A source array 192 emits diffused waves that propagate in tissue195 and are detected by detectors 200. The highest resolution isachieved when a hidden object is located on the null line of thediffused waves. The system operates at about 50 MHz, to use instead ofthe laser diodes LED's and instead of the PMT detectors Si diodes.oscillators 202 and 204 drive phase splitters 206 and 208, respectively,that provide two intensity modulated voltage signals shifted 180° withrespect to each other. The 0° and 180° signals drive 750 nm and 850 nm,LED sources which are multiplexed by switches 210 and 212 to operatesources of one wavelength at the same time. The modulated diffuse wavesare detected by the Si diodes that include a wavelength specificinterference filter, and the detector signal are converted from 50 MHzand 50.01 MHz frequencies to 20 kHz frequencies using mixers 226 and228, respectively. Phase detectors 230 and 232 operating at 20 kHzdetermine the phase shift of the detected signals. Both the phase shiftsignals and the amplitude signals are used to image the hidden absorberon a display unit 240.

[0122] A 2-dimensional transmitter and receiver arrays are shown in FIG.12A. The spacing of the input ports can be varied depending on thefrequency of operation, expected location of the hidden object and theshape of the examined organ. FIG. 12B shows diagrammatically an imagingsystem utilizing the 2-dimensional transmitter and receiver arrays 250and 255 that can be switched on electronically. A master oscillator 262and a laser driver 260 drive a pair of in-phase and anti-phase laserdiodes, e.g., the first and the third diode of Y-array and Z-array. Aset of electronic switches is used to connect a different set of laserdiodes every 10 msec. A set of optical fibers transmits the detectedlight to a PMT detector 264 that also receives a reference 200.025 MHzsignal from a local oscillator 266.

[0123] The heterodyned resulting signal is sent to a phase detector 272that measures the phase shift of the detected radiation. The measuredphase shift is further manipulated to enhance the detected changes on aCRT display 276 which has the same 10 msec time base as electronicswitches 263. Differenciator 274 takes a derivative of the phase shiftsignal; this intensifies the crossover of the phase shift shown in FIGS.8c, 9 c and 9 d.

Alternative Embodiments

[0124] In addition to the above described directional detection, thepresent invention envisions imaging systems constructed to calculate theaverage migration pathlengths. Referring to FIG. 4, in such system thedrive signal from oscillator 60 is introduced to a selected laser diode64 a, . . . , 64 n or 66 a, . . . , 66 n using switches 61 a, . . . , 61n. The intensity modulated radiation of each laser diode is coupled totissue 70 at an input port located at a precisely defined position. Adetection port located at another position detects radiation that hasmigrated in tissue 70. The detected signal is heterodyne mixed directlyat PMT detector 74. These signals are fed into the phase detectorwherein the phase and the intensity of the detected radiation aremeasured. The system may include several PMT detectors and phasedetectors (only one set of detectors is shown in FIG. 4) operatingsimultaneously or one detector scans the surface of tissue 70. The phaseshift and the intensity of the detected heterodyned signal depend on thetissue through which said scattered and absorbed radiation migrated.

[0125] The tissue properties are determined from the detected phaseshift and intensity values and from the known input ports and detectionport geometries. The measured average pathlengths, <L>, can also bedetermined. The detected phase shift is converted to an effectivemigration pathlength <L> by using the low frequency approximationθ=2πf<L>n/c, wherein f is the modulation frequency, c is the speed oflight (3×10⁸ cm/s), and n is the refractive index of the medium.

[0126] To illustrate imaging by detecting migration pathlengths, we usean example of photon migration in a tissue with a strongly absorbingobject, a perfect absorber(μ_(a)→∞) of radius R. Referring to FIGS. 5A,5B, and 5C the distribution of pathlengths defines an optical field thatexists between a point detector, D, and source, S, separated by distanceρ and located on the exterior of an examined tissue which is asemi-infinite, strongly scattering medium. As shown in FIG. 5A,infinitely far away from the field, a perfect absorber does not alterthe banana-shaped optical field of photons emitted by source S anddetected at detector D. As the object enters the optical field (FIG.5B), the photons which have migrated the farthest distance from D and Sare eliminated by the absorption process inside the perfect absorber ofradius R. Since photons which travel the longest pathlengths areabsorbed, the approach of an object shortens the distribution ofpathlengths, or alternatively, shortens the average pathlength <L>. Asthe object moves closer, and the optical field surrounds the object(FIG. 5C), some of the detected photons have travelled “around” theobject, which is detected as lengthening the distribution ofpathlengths. Thus, the average pathlength measurement can reveallocation of a strongly absorbing component of a tissue (e.g., tumor orlocalized bleeding).

[0127] Even though this pathlength computation approach requires in mostcases extensive computational capabilities, it can yield usefulinformation in the localization procedures and can provide an usefulsupplement to the above described directional approach.

What is claimed is:
 1. A method of spectroscopic examination of asubject positioned between input and detection ports of a spectroscopicsystem applied to the subject, said method comprising: (a) providingmultiple input ports placed at selected locations on the subject toprobe a selected quality of the subject, (b) introducing into thesubject, at said input ports, electromagnetic non-ionizing radiation ofa wavelength selected to be scattered and absorbed while migrating inthe subject, said radiation at each of said input ports having a knowntime-varying pattern of photon density, (c) the time relationship ofsaid patterns being selected to form resulting radiation that possessessubstantial gradient in photon density as a result of the interaction ofthe introduced patterns emanating from said input ports, said resultingradiation being scattered and absorbed in migration paths in thesubject, (d) detecting over time, at a detection port placed at aselected location on the subject, said radiation that has migrated inthe subject, (e) processing signals of said detected radiation inrelation to said introduced radiation to create processed dataindicative of the influence of said subject upon said gradient of photondensity, and (f) examining said subject by correlating said processeddata with the locations of said input and output ports.
 2. The method ofclaim 1 further comprising (a) moving synchronously said input ports orsaid detection port to a different location on a predetermined geometricpattern, (b) at said different location, further introducing into thesubject, at said input ports, electromagnetic non-ionizing radiation ofa wavelength selected to be scattered and absorbed while migrating inthe subject, said radiation at each of said input ports having a knowntime-varying pattern of photon density, (c) the time relationship ofsaid -patterns being selected to form resulting radiation that possessessubstantial gradient in photon density as a result of the interaction ofthe introduced -patterns emanating from said input ports, said resultingradiation being scattered and absorbed in migration paths in thesubject, (d) detecting over time, at said detection port placed at aselected location on the subject, said further introduced radiation thathas migrated in the subject, and (e) processing signals of said detectedfurther introduced radiation in relation to said introduced radiation tocreate processed data indicative of the influence of said subject uponsaid gradient of photon density.
 3. A method of spectroscopicexamination of a subject positioned between input and detection ports ofa spectroscopic system applied to the subject, said method comprising:(a) providing multiple input ports placed at selected locations on thesubject to probe a selected quality of the subject, (b) introducing intothe subject, at said input ports, electromagnetic non-ionizing radiationof a wavelength selected to be scattered and absorbed while migrating inthe subject, said radiation at each of said input ports having a knowntime-varying pattern of photon density, (c) the time relationship ofsaid patterns being selected to form resulting radiation that possessessubstantial gradient in photon density as a result of the interaction ofthe introduced patterns emanating from said input ports, said resultingradiation being scattered and absorbed in migration paths in thesubject, (d) detecting over time, at a detection port placed at aselected location on the subject, said radiation that has migrated inthe subject, (e) processing signals of said detected radiation inrelation to said introduced radiation to create processed dataindicative of the influence of said subject upon said gradient of photondensity, (f) moving said detection port to a second location on thesubject, (g) detecting over time, at said detection port placed at saidsecond location on the subject, said radiation that has migrated in thesubject, (h) processing signals of said radiation, detected at secondlocation, in relation to said introduced radiation to create processeddata indicative of the influence of said subject upon said gradient ofphoton density, and (i) examining said subject by correlating saidprocessed data with the locations of said input and output ports.
 4. Themethod of claim 3 further comprising (a) moving said detection port todifferent locations on a predetermined geometric pattern, (b) detectingover time, at said detection port placed at a selected location on thesubject, said radiation that has migrated in the subject, and (c)processing signals of said radiation, detected at said differentlocations, in relation to said introduced radiation to create processeddata indicative of the influence of said subject upon said gradient ofphoton density.
 5. The method of claim 2, 3 or 4 wherein said timerelationship is further selected to vary the spatial orientation of saidgradient of photon density and said movement of said detection portmaintains a fixed relationship of said detection port to said varyingorientation of said gradient of photon density.
 6. A method ofspectroscopic examination of a subject positioned between input anddetection ports of a spectroscopic system applied to the subject, saidmethod comprising: (a) providing multiple input ports placed at selectedlocations on the subject to probe a selected quality of the subject, (b)introducing into the subject, at said input ports, electromagneticnon-ionizing radiation of a wavelength selected to be scattered andabsorbed while migrating in the subject, said radiation at each of saidinput ports having a known time-varying pattern of photon density, (c)the time relationship of said patterns being selected to form resultingradiation that possesses substantial gradient in photon density as aresult of the interaction of the introduced patterns emanating from saidinput ports, said resulting radiation being scattered and absorbed inmigration paths in the subject, (d) providing multiple detection portsplaced on selected locations on the subject, to probe a selected qualityof the subject, (e) detecting over time, at said detection ports, saidradiation that has migrated in the subject, (f) processing signals ofsaid detected radiation in relation to said introduced radiation tocreate processed data indicative of the influence of said subject uponsaid gradient of photon density, and (f) examining said subject bycorrelating said processed data with the locations of said input andoutput ports.
 7. The method of claim 6 further comprising (a) moving atleast one said detection port to a different location on a predeterminedgeometric pattern, (b) detecting over time, said different location onthe subject, radiation that has migrated in the subject, and (c)processing signals of said radiation, detected at said differentlocation, in relation to said introduced radiation to create processeddata indicative of the influence of said subject upon said gradient ofphoton density.
 8. The method of claim 6 wherein said input ports placedon said subject are disposed in array and said method further comprises:(a) rotating said array of input ports while introducing said radiationinto the subject at said input ports, (b) detecting over time, at saiddetection ports, said resulting radiation that has migrated in thesubject, and (c) processing signals of said detected radiation inrelation to said introduced radiation to create processed dataindicative of the influence of said subject upon said gradient of photondensity.
 9. The method of claim 1, 2, 3, 4, 5, 6, 7 or 8 wherein saidsubject comprises a constituent that fluoresces, said wavelength of saidintroduced radiation selected to be absorbed in said fluorescentconstituent, said detected radiation is emitted from said fluorescentconstituent and processed to determine location of said fluorescentconstituent.
 10. A method of spectroscopic examination of a subjectpositioned between input and detection ports of a spectroscopic systemapplied to the subject, said method comprising: (a) providing an inputport placed at selected locations on the subject to probe a selectedquality of the subject, (b) introducing into the subject, at said inputport electromagnetic non-ionizing radiation of a wavelength selected tobe scattered and absorbed while migrating in the subject, said radiationhaving a known time-varying pattern of photon density, (c) providingmultiple detection ports placed on selected locations on the subject, toprobe a selected quality of the subject, (d) detecting over timeradiation that has migrated in the subject, the time relationship ofsaid detection over time, at said detection ports, being selected toobserve gradient in photon density formed as a result of the interactionof the introduced radiation with the subject, (e) processing signals ofsaid detected radiation in relation to said introduced radiation tocreate processed data indicative of the influence of said subject uponsaid gradient of photon density, and (f) examining said subject bycorrelating said processed data with the locations of said input andoutput ports.
 11. The method of claim 10 further comprising (a) movingsaid detection ports to a different location on a predeterminedgeometric pattern, (b) detecting over time resulting radiation that hasmigrated in the subject, the time relationship of said detection overtime, at said detection ports, being selected to observe gradient inphoton density formed as a result of the interaction of the introducedradiation with the subject, and (c) processing signals of said detectedradiation in relation to said introduced radiation to create processeddata indicative of the influence of said subject upon said gradient ofphoton density.
 12. A method of spectroscopic examination of a subjectpositioned between input and detection ports of a spectroscopic systemapplied to the subject, said method comprising: (a) providing an inputport placed at selected locations on the subject to locate a fluorescentconstituent in the subject, (b) introducing into the subject, at saidinput port electromagnetic non-ionizing radiation of a wavelengthselected to be scattered and absorbed by said constituent whilemigrating in the subject, said radiation having a known time-varyingpattern of photon density, (c) providing multiplicity of detection portsplaced on selected locations on the subject to locate a fluorescentconstituent of the subject, (d) detecting over time fluorescentradiation that has migrated in the subject, (e) processing signals ofsaid detected radiation in relation to said introduced radiation tocreate processed data indicative of location of said fluorescentconstituent of the subject, and (f) determining location of saidfluorescent constituent of the subject by correlating said processeddata with the locations of said input and output ports.
 13. The methodof claim 12 further comprising (a) moving said detection ports to adifferent location on a predetermined geometric pattern, (b) detectingover time said fluorescent radiation that has migrated in the subject,and (c) processing signals of said radiation detected at said differentlocation in relation to said introduced radiation to create processeddata indicative of location of said fluorescent constituent of thesubject.
 14. The method of claim 1, 2, 3, 4, 5, 6, 7 or 8 wherein saidtime-varying pattern comprises radiation of said selected wavelengthintensity modulated at a selected frequency, said modulated radiationwhen introduced from each of said input ports having selected phaserelationship that produces in at least one direction a steep phasechange and a sharp minimum in the intensity of said radiation.
 15. Themethod of claim 14 wherein said phase relationship is 180 degrees. 16.The method of claim 14 or 15 further comprising a step of imposing onall said introduced radiation patterns an identical time-varying phasecomponent thereby changing the spatial orientation of said direction ofsaid steep phase change and said sharp minimum in the intensity of saidradiation.
 17. The method of claim 1, 2, 3, 4, 5, 6, 7 or 8 wherein saidtime-varying pattern comprises radiation of said selected wavelengthintensity modulated at a selected frequency, said modulated radiationwhen introduced from each of said input ports having selected frequencyrelationship that produces in at least one direction a steep phasechange and a sharp minimum in the intensity of said radiation.
 18. Themethod of claim 1, 2, 3, 4, 5, 6, 7 or 8 wherein said time-varyingpattern comprises radiation of said selected wavelength intensitymodulated at a selected frequency, said modulated radiation whenintroduced from each of said input ports having selected amplituderelationship that produces in at least one direction a steep phasechange and a sharp minimum in the intensity of said radiation.
 19. Themethod of claim 18 further comprising a step of imposing on all saidintroduced radiation patterns an identical time-varying amplitudecomponent thereby changing the spatial orientation of said direction ofsaid steep phase change and said sharp minimum in the intensity of saidradiation.
 20. The method of claim 14, 15, 16, 17, 18 or 19 wherein saidradiation is modulated at a frequency that enables resolution of thephase shift that originates during migration of photons in the subject.21. The method of claim 20 wherein said frequency is on the order of 10⁸Hz.
 22. The method of claim 1, 2, 3, 4, 6, 7, 9, 10, 11, 12 or 13wherein said processing comprises determining the phase or the amplitudeof said radiation altered by scattering and absorption in the subject.23. The method of claim 22 said phase or said amplitude are employed insaid examining step to localize a hidden object in said subject.
 24. Themethod of claim 22 said phase or said amplitude are employed in saidexamining step to image components of said subject.
 25. The method ofclaim 1, 2, 3, 4, 5, 6, 7, 9 or 10 wherein said wavelength of saidradiation is susceptible to changes in an endogenous or exogenous tissuepigment of the subject.
 26. A system for spectroscopic examination of asubject, positioned between input and detection ports of thespectroscopic system applied to the subject, comprising: at least onelight source adapted to introduce, at multiple input ports,electromagnetic non-ionizing radiation of a known time-varying patternof photon density and of a wavelength selected to be scattered andabsorbed while migrating in the subject, said input ports being placedat selected locations on the subject to probe a selected quality of thesubject, radiation pattern control means adapted to achieve a selectedtime relationship of said introduced patterns to form resultingradiation that possesses substantial gradient in photon density as aresult of the interaction of the introduced patterns emanating from saidinput ports, said radiation being scattered and absorbed in migrationpaths in the subject, a detector adapted to detect over time, at adetection port placed at a selected location on the subject, saidradiation that has migrated in the subject, processing means adapted toprocess signals of said detected radiation in relation to saidintroduced radiation to create processed data indicative of theinfluence of said subject upon said gradient of photon density, andevaluation means adapted to examine the subject by correlating saidprocessed data with the locations of said input and output ports. 27.The system of claim 26 further comprising displacement means adapted tomove synchronously said optical ports and said detection ports toanother location on a predetermined geometric pattern, said otherlocation being used to perform said examination of the subject.
 28. Asystem for spectroscopic examination of a subject, positioned betweeninput and detection ports of the spectroscopic system applied to thesubject, comprising: at least one light source adapted to introduce, atmultiple input ports, electromagnetic non-ionizing radiation of a knowntime-varying pattern of photon density and of a wavelength selected tobe scattered and absorbed while migrating in the subject, said inputports being placed at selected locations on the subject to probe aselected quality of the subject, radiation pattern control means adaptedto achieve selected time relationship of said introduced patterns toform resulting radiation that possesses substantial gradient in photondensity as a result of the interaction of the introduced patternsemanating from said input ports, said radiation being scattered andabsorbed in migration paths in the subject, a detector adapted to detectover time, at a detection port placed at a selected location on thesubject, said radiation that has migrated in the subject, displacementmeans adapted to move said detection port to various locations on apredetermined geometric pattern, said various locations being used todetect over time radiation that has migrated in the subject, processingmeans adapted to process signals of said detected radiation in relationto said introduced radiation to create processed data indicative of theinfluence of said subject upon said gradient of photon density, andevaluation means adapted to examine the subject by correlating saidprocessed data with said locations of said input and output ports. 29.The system of claim 27 or 28 wherein said radiation pattern controlmeans are further adapted to modify said time relationship to vary thespatial orientation of said gradient of photon density and saiddisplacement means further adapted to maintain a fixed relationship ofsaid detection port to said varying orientation of said gradient ofphoton density.
 30. A system for spectroscopic examination of a subject,positioned between input and detection ports of spectroscopic systemapplied to the subject, comprising: at least one light source adapted tointroduce, at multiple input ports, electromagnetic non-ionizingradiation of a known time-varying pattern of photon density and of awavelength selected to be scattered and absorbed while migrating in thesubject, said input ports being placed at selected locations on thesubject to probe a selected quality of the subject, radiation patterncontrol means adapted to achieve selected time relationships of saidintroduced patterns to form resulting radiation that possessessubstantial gradients in photon density as a result of the interactionof the introduced patterns emanating from said input ports, saidradiation being scattered and absorbed in migration paths in thesubject, at least one detector adapted to detect over time, at multipledetection ports placed at a selected locations on the subject, saidradiation that has migrated in the subject, processing means adapted toprocess signals of said detected radiation in relation to saidintroduced radiation to create processed data indicative of theinfluence of said subject upon said gradient of photon density, andevaluation means adapted to examine the subject by correlating saidprocessed data with the locations of said input and output ports. 31.The system of claim 30 further comprising displacement means adapted tomove at least one of said detection ports to another location on apredetermined geometric pattern, said other location being used toperform said examination of the subject.
 32. The system of claim 30further comprising rotation means adapted to rotate synchronously saidoptical input ports while introducing said resulting radiation along apredetermined geometric pattern, said input port rotation being used toperform said examination of a region of the subject.
 33. The system ofclaim 26, 27, 28, 29, 30, 31 or 32 wherein the subject comprises afluorescent constituent of interest, said wavelength of said introducedradiation is selected to be absorbed in said fluorescent constituent,said detected radiation is emitted from said fluorescent constituent andprocessed to determine location of said fluorescent constituent.
 34. Asystem for spectroscopic examination of the subject, positioned betweeninput and detection ports of a spectroscopic system applied to thesubject, comprising: a light source adapted to introduce, at an inputport, electromagnetic non-ionizing radiation of a known time-varyingpattern of photon density and of a wavelength selected to be scatteredand absorbed while migrating in the subject, said input port beingplaced at a selected location on the subject to probe a selected qualityof the subject, detectors adapted to detect over time, at multipledetection ports placed at selected locations on the subject, saidradiation that has migrated in the subject, the time relationship ofsaid detection over time, at said detection ports, being selected toobserve gradient in photon density formed as a result of the interactionof the introduced radiation with the subject, processing means adaptedto process signals of said detected radiation in relation to saidintroduced radiation to create processed data indicative of theinfluence of said subject upon said gradient of photon density, andevaluation means adapted to examine said subject by correlating saidprocessed data with the locations of said input and output ports. 35.The system of claim 34 further comprising displacement means adapted tomove at least one of said detection ports to another location on apredetermined geometric pattern, said other location being used toperform said examination of the subject.
 36. A system for spectroscopicexamination of a subject, positioned between input and detection portsof the spectroscopic system applied to the subject, comprising: a lightsource adapted to introduce, at an input port, electromagneticnon-ionizing radiation of a known time-varying pattern of photon densityand of a wavelength selected to be scattered and absorbed by afluorescent constituent while migrating in the subject, said input portbeing placed as a selected location on the subject to locate saidfluorescent constituent of the subject, detectors adapted to detect overtime, at multiple detection ports placed at selected locations on thesubject, fluorescent radiation that has migrated in the subject,processing means adapted to process signals of said detected radiationin relation to said introduced radiation to create processed dataindicative of location of said fluorescent constituent of the subject,and evaluation means adapted to examine said subject by correlating saidprocessed data with the locations of said input and output ports. 37.The system of claim 36 further comprising displacement means adapted tomove at least one of said detection ports to another location on apredetermined geometric pattern, said other location being used tolocate said fluorescent constituent of the subject.
 38. The system ofclaim 26, 27, 27, 29, 30, 31 or 32 wherein said time-varying patterncomprises radiation of a selected wavelength intensity modulated at saidselected frequency, and said radiation pattern control means are furtheradapted to control a selected phase relationship between said modulatedradiation patterns introduced from each of said input ports having toproduce in at least one direction a steep phase change and a sharpminimum in the intensity of said radiation.
 39. The system of claim 38wherein said phase relationship is 180 degrees.
 40. The system of claim38 or 39 wherein said radiation pattern control means are furtheradapted to impose on all said introduced radiation patterns an identicaltime-varying phase component thereby changing the spatial orientation ofsaid direction of said steep phase change and said sharp minimum in theintensity of said radiation.
 41. The system of claim 26, 27, 27, 29, 30,31 or 32 wherein said time-varying pattern comprises radiation of aselected wavelength intensity modulated at said selected frequency, andsaid radiation pattern control means are further adapted to control aselected frequency relationship between said modulated radiationpatterns introduced from each of said input ports having to produce inat least one direction a steep phase change and a sharp minimum in theintensity of said radiation.
 42. The system of claim 26, 27, 27, 29, 30,31 or 32 wherein said time-varying pattern comprises radiation of aselected wavelength intensity modulated at said selected frequency, andsaid radiation pattern control means are further adapted to control aselected amplitude relationship between said modulated radiationpatterns introduced from each of said input ports having to produce inat least one direction a steep phase change and a sharp minimum in theintensity of said radiation.
 43. The system of claim 42 wherein saidradiation pattern control means are further adapted to add to all saidintroduced radiation patterns an identical time-varying amplitudecomponent thereby changing the spatial orientation of said direction ofsaid steep phase change and said sharp minimum in the intensity of saidradiation.
 44. The system of any one of claims 38 through 43 whereinsaid radiation is modulated at a frequency that enables resolution ofthe phase shift that originates during migration of photons in thesubject.
 45. The system of claim 44 wherein said frequency is on theorder of 10⁸ Hz.
 46. The system of claim 26, 27, 28, 29, 30, 31, 32, 34or 35 wherein said processing means further adapted to determine thephase or the intensity of said radiation altered by scattering andabsorption in the subject.
 47. The system of claim 26, 27, 28, 29, 30,31, 32, 34 or 35 wherein said wavelength of said radiation issusceptible to changes in an endogenous or exogenous tissue pigment ofthe subject.